A Phase 1/2 Study of the Oral ALK/EGFR Inhibitor AP26113

Conditions

Trial Phase

Phase 1/Phase 2

Trial Purpose and Description

Trial Purpose

The purpose of this study is 2-fold: initially, in the dose escalation phase, the goal is to determine the safety profile of orally administered AP26113, including: the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile. Then, once the RP2D is established, an expansion phase will assess the preliminary anti-tumor activity of AP26113, both in non-small cell lung cancer (NSCLC) with ALK gene rearrangement (including patients with active brain metastases)or mutated EGFR, and in other cancers with abnormal targets against which AP26113 is active. Approximately 135 to 175 patients will be enrolled.

Trial Description

This is the first assessment of AP26113 in patients. The trial will be conducted in 2 parts: an initial dose escalation phase in 30 to 70 patients with advanced malignancies (all histologies other than leukemia), resistant to available therapies or for whom no standard or available curative treatments exist, followed by an expansion phase in 5 histologically and molecularly defined cohorts of patients (approximately 20-25 patients per cohort, approximately 105 patients altogether). The objectives of the dose escalation phase are to determine the safety, tolerability, pharmacokinetic profile, and recommended phase 2 dose (RP2D) of orally administered AP26113. The objectives of the expansion phase are to describe the preliminary anti-tumor activity (overall response rate) of AP26113 in patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene rearrangement or mutated epidermal growth factor receptor (EGFR), and in patients with any cancers with abnormalities in ALK or other targets against which AP26113 is active, and to continue to assess safety and tolerability.

Participation Guidelines

Age:

18 Years - N/A

Gender:

Both

Eligibility Criteria

Patients must meet all the criteria for the cohort for which their entry is proposed.

- Neurologically stable. Patients must be on a stable or deceasing dose of corticosteroids and/or have no requirement for anticonvulsants for 5 days prior to the baseline MRI and for 5 days prior to initiating AP26113.

General Eligibility Criteria:

All patients (irrespective of whether they are enrolled in PART 1 or PART 2) must meet all the following eligibility criteria for study entry.

- All patients must have tumor tissue available for analysis. If sufficient tissue is not available, patients must undergo a biopsy to obtain adequate samples. For patients in expansion cohorts 2, 3 and 5, for whom failure of prior therapy is specified (crizotinib for cohorts 2 and 5, one EGFR-TKI for cohort 3),tumor tissue must be available following failure of the prior therapy.

- Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).

- For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.

- Female patients who are of childbearing potential and fertile male patients must agree to use an effective form of contraception with their sexual partners throughout study participation.

- Signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study.

- Willingness and ability to comply with scheduled visits and study procedures.

Main Exclusion Criteria:

- Received an investigational agent = 14 days prior to initiating AP26113.

- Received systemic anticancer therapy (including monoclonal antibodies and irreversible TKIs such as afatinib or dacomitinib) or radiation therapy = 14 days prior to initiating AP26113.

- Except for a reversable TKI (ie, erlotinib or gefitinib) or crizotinib, which are allowed up to 72 hours prior to initiating AP26113, provided that the patient is free of treatment-related toxicity that might confound the safety evaluation of AP26113.

- Received any prior agents targeted against ALK, with the exception of crizotinib, or received more than 1 prior EGFR TKI.

- Re-challenge with the same TKI is allowed.

- Major surgery within 28 days prior to initiating AP26113.

- Brain metastases that are neurologically unstable or require anticonvulsants or an increasing dose of corticosteroids.

- Patients with previously treated brain metastases without evidence of disease or recurrence are allowed for cohorts 1-4.

- Patients with evaluable but non-measurable, active brain lesions who otherwise meet the criteria for cohort 5 for CNS disease can be enrolled in other cohorts.